ABSTRACT
INTRODUCTION: Identifying polymorphisms in the dihydropyrimidine dehydrogenase (DPYD) gene is gaining importance to be able to predict fluoropyrimidine-associated toxicity. The aim of this project was to describe the frequency of the DPYD variants DPYD*2A (rs3918290); c.1679T>G (rs55886062); c.2846A>T (rs67376798) and c.1129-5923C>G (rs75017182; HapB3) in the Spanish oncological patients. MATERIAL AND METHODS: Cross-sectional and multicentric study (PhotoDPYD study) conducted in hospitals located in Spain designed to register the frequency of the most relevant DPYD genetic variants in oncological patients. All oncological patients with DPYD genotype were recruited in the participant hospitals. The measures determined where the presence or not of the 4 DPYD previously described variants. RESULTS: Blood samples from 8054 patients with cancer from 40 different hospitals were used to determine the prevalence of the 4 variants located in the DPYD gene. The frequency of carriers of one defective DPYD variant was 4.9%. The most frequently identified variant was c.1129-5923C>G (rs75017182) (HapB3), in 2.9%, followed by c.2846A>T (rs67376798) in 1.4%, c.1905 + 1G>A (rs3918290, DPYD*2A) in 0.7% and c.1679T>G (rs55886062) in 0.2% of the patients. Only 7 patients (0.08%) were carrying the c.1129-5923C>G (rs75017182) (HapB3) variant, 3 (0.04%) the c.1905 + 1G>A (rs3918290, DPYD*2A) and one (0.01%) the DPYD c.2846A>T (rs67376798, p.D949V) variant in homozygosis. Moreover, 0.07% were compound heterozygous patients, 3 carrying the DPYD variants DPYD*2A + c.2846A>T, 2 the DPYD c.1129-5923C>G + c.2846A>T and one the DPYD*2A + c.1129-5923C>G variants. CONCLUSIONS: Our results demonstrate the relatively high frequency of DPYD genetic variants in the Spanish patient with cancer population, which highlights the relevance of their determination before initiating a fluoropirimidine-containing regimen.
Subject(s)
Dihydrouracil Dehydrogenase (NADP) , Neoplasms , Humans , Cross-Sectional Studies , Dihydrouracil Dehydrogenase (NADP)/genetics , Fluorouracil , Genotype , Neoplasms/epidemiology , Neoplasms/genetics , Polymorphism, Genetic , Spain/epidemiologyABSTRACT
WHAT IS KNOWN AND OBJECTIVE: Cancer is one of the most important causes of morbidity and mortality worldwide. Pro-, pre- and symbiotics can modulate host metabolism and gut microbiota and potentially help prevent cancer and modulate the adverse effects (AEs) of treatments. Numerous studies on this role for pro-, pre- and symbiotics have reported inconsistent results. The purpose of this review was to examine current scientific evidence from randomized controlled trials (RCTs) on the effects of pro-, pre- and symbiotics on the incidence of complications and AEs, especially diarrhoea, in cancer management. METHODS: A systematic literature search was implemented in MEDLINE using the MeSH terms "probiotics", "prebiotics", "symbiotics" and "neoplasms", according to PRISMA guidelines. Reference lists were also handsearched to identify additional eligible RCTs. Three reviewers independently assessed the eligibility of each RCT. Of 714 retrieved abstracts, 22 articles with 2287 participants were included in the analysis. RESULTS AND DISCUSSION: The most studied bacteriotherapies were probiotics and symbiotics, in 10 and 7 studies, respectively. Both Lactobacillus and Bifidobacterium strains were used in 18 studies, while Lactobacillus and Bifidobacterium strains were individually used in 9 and 2 studies, respectively. Diarrhoea incidence rates were 3.2%-39.1% in intervention groups and 6.7%-60.9% in control groups, while infection incidence rates were 11.1%-22.7% in intervention groups and 17.3%-28.7% in control groups. WHAT IS NEW AND CONCLUSIONS: Pro-, pre- and symbiotics may potentially be efficacious in reducing complications associated with chemotherapy, radiotherapy and surgery in patients with cancer.
Subject(s)
Neoplasms/drug therapy , Prebiotics/administration & dosage , Probiotics/administration & dosage , Humans , Randomized Controlled Trials as TopicABSTRACT
WHAT IS KNOWN AND OBJECTIVE: Tocilizumab is an IL-6 receptor inhibitor agent which has been proposed as a candidate to stop the inflammatory phase of infection by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, safety data of tocilizumab in pregnant women and their newborn are scarce. We aimed to describe maternal and neonatal safety outcomes associated with tocilizumab treatment in pregnant women with severe COVID-19. METHODS: This is a retrospective study of severe COVID-19 pregnant women, treated with tocilizumab in two Spanish hospitals between 1 March and 31 April 2020. Demographics, medical history, clinical and radiologic findings, treatment information and laboratory data of mothers and their newborns were collected from electronic medical records. RESULTS AND DISCUSSION: A total of 12 pregnant women were identified to have received tocilizumab during pregnancy in the two hospitals. Median gestational age at admission was 27.7 weeks (interquartile range, 18.0-36.4). Most of them received lopinavir/ritonavir, azithromycin and hydroxychloroquine, two patients received corticosteroids and one received interferon beta 1B. All 12 pregnancies resulted in live births. Somatometric values were normal for all newborns, and evolution at 14 and 28 days was favourable for all of them. Hepatotoxicity was observed in 2 patients, which improved or resolved at discharge. Cytomegalovirus reactivation was detected in another patient who had also received corticosteroids for 15 days, causing a congenital infection in her newborn. Both hepatotoxicity and viral reactivation adverse events were classified as possibly related to tocilizumab administration according to Naranjo's causality algorithm. WHAT IS NEW AND CONCLUSIONS: It does not appear that tocilizumab has detrimental effects for the mother and newborn. Close monitoring of infections should be considered, especially if other immunosuppressive agents are used.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 Drug Treatment , Pregnancy Complications, Infectious/drug therapy , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Female , Humans , Infant, Newborn , Pregnancy , Retrospective Studies , SARS-CoV-2 , Severity of Illness Index , Spain , Treatment OutcomeABSTRACT
OBJECTIVE: The purpose of this systematic review was to examine the effect of antipsychotic medication on dysphagia based on clinical case reports. PATIENTS AND METHODS: Literature searches were performed using the electronic databases PubMed and Embase. In PubMed, we used the MeSH terms "antipsychotic agents" OR "tranquilizing agents" combined with "deglutition disorders" OR "deglutition". In Embase, we used the Emtree terms "neuroleptic agents" combined with "swallowing" OR "dysphagia". Two reviewers assessed the eligibility of each case independently. RESULTS: A total of 1043 abstracts were retrieved, of which 36 cases met the inclusion criteria; 14 cases were related to typical antipsychotics and 22 to atypical antipsychotics. Dysphagia occurred together with extrapyramidal symptoms in half of the cases and was the only prominent symptom in the other half. The most common strategy against dysphagia was changing to another antipsychotic (n=13, 36.1%). CONCLUSIONS: The data from this review indicate that antipsychotics can increase the prevalence of dysphagia.
Subject(s)
Antipsychotic Agents/adverse effects , Deglutition Disorders/chemically induced , Humans , Medical RecordsABSTRACT
PURPOSE: Antipsychotics (APs) are commonly used to manage neuropsychiatric symptoms (NPS) in elderly patients with dementia, even though several large studies have demonstrated an association between AP treatment and increased morbidity and mortality in people with dementia. The aim of this study is to review the scientific literature of the use of AP in the elderly with dementia and to propose an algorithm to assist in decision-making regarding the withdrawal of APs. METHODS: A computerized literature search (MEDLINE: 1966 to December 2016, EMBASE: 1982 to December 2016) was used to locate relevant literature. Keywords in the search included terms from Medical Subject Headings (MESH) and EMBASE thesaurus (EMTREE). The following terms were used in the MESH database and EMTREE thesaurus: Aged, Antipsychotic Agents, Behavioral Symptoms and Dementia. RESULTS: Earlier studies of APs used in elderly patients with dementia suggest that, in most elderly demented patients, APs can be withdrawn with no effect on behaviour. These patients are likely to benefit from the algorithm we propose to assist clinicians in the withdrawal of APs. CONCLUSIONS: In this paper, we review the potential risks and benefits of discontinuing AP treatment in elderly demented patients with NPS and propose an algorithm to assist in decision-making regarding AP withdrawal.
Subject(s)
Algorithms , Antipsychotic Agents/therapeutic use , Decision Making , Dementia/drug therapy , Aged , HumansSubject(s)
COVID-19 , Organ Transplantation , Humans , Organ Transplantation/adverse effects , SARS-CoV-2 , Transplant RecipientsABSTRACT
Scientific evidence on the impact of medication on the physiology of swallowing is scarce and mainly based on clinical case reports. To evaluate the association between oropharyngeal dysphagia (OD) and chronic exposure to medication in older patients admitted to the acute geriatric unit (AGU) of a secondary hospital, we performed a retrospective cross-sectional study of 966 patients admitted to an AGU from 2008 to 2011. We reviewed (a) diagnosis of OD (assessed with the volume-viscosity swallow test, V- VST); (b) chronic patient medication classified by anatomical, therapeutic, chemical codes; and (c) demographic and clinical data. A univariate analysis was performed to determine which medications were associated with OD. A multivariate analysis adjusting for confounding clinical factors was performed to identify which of those medications were independently associated with OD. The age of patients included was 85.3 ± 6.37 years and 59.4 % were women. A total of 41.9 % presented OD. We found a possible protective effect of beta blocking agents on OD after the multivariate analysis (OR 0.54, 95 % CI 0.35-0.85). None of the categories of drugs was associated with an altered swallowing function after adjusting for confounding variables. The present study is the first one to widely investigate the association between drugs and OD, increasing understanding of their association. The role of beta blockers in OD needs to be further studied as their potentially beneficial effects on the swallowing function in older patients could help to prevent complications.
Subject(s)
Adrenergic beta-Antagonists/adverse effects , Deglutition Disorders/chemically induced , Aged , Aged, 80 and over , Cross-Sectional Studies , Deglutition/drug effects , Female , Humans , Male , Multivariate Analysis , Retrospective StudiesABSTRACT
OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre-dose and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (SD 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (p=0.002) and decreased serum creatinine at both higher pre- and post-dose concentrations (p=0.001 and p=0.017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 µg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% CV) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.
Subject(s)
Atypical Hemolytic Uremic Syndrome , Adult , Humans , Child , Middle Aged , Atypical Hemolytic Uremic Syndrome/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , SpainABSTRACT
OBJECTIVE: The objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. METHODS: Observational, ambispective, and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in 5 hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre- and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. RESULTS: Twenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (interquartile range (IQR) 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre- and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) µg/mL and 747.4 (standard deviation (SD) 444.3) µg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (Pâ¯=â¯.002) and decreased serum creatinine at both higher pre- and post-dose concentrations (Pâ¯=â¯.001 and Pâ¯=â¯.017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0⯵g/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% variation coefficient (CV)) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. CONCLUSIONS: The present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.
Subject(s)
Atypical Hemolytic Uremic Syndrome , Adult , Humans , Child , Middle Aged , Atypical Hemolytic Uremic Syndrome/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , SpainABSTRACT
Hyponatremia on admission has been related to worse outcomes in patients with COVID-19 infection. However, little is known about the frequency and the associated risk factors of hyponatremia after COVID-19 discharge. We performed an observational 24-month follow-up study of patients admitted during the first COVID-19 wave. Kaplan-Meier curves and Cox proportional hazard models were used to assess the main variables in predicting hyponatremia on follow-up (HYPO-FU). A total of 161 out of 683 (24.4%) developed HYPO-FU. The group with HYPO-FU comprised of more men [(62.3%) vs. (49.2%); p < 0.01], older [65.6 ± 18.2 vs. 60.3 ± 17.0; p < 0.01] and more frequently re-admitted [(16.2%) vs. (3.8%); p < 0.01). The rate of HYPO-FU was higher in the first year 23.6 per 100 individuals per year. After Cox regression analysis, the independent risk factors of HYPO-FU were diabetes [OR 2.12, IC 95% (1.48-3.04)], hypertension [OR 2.18, IC 95% (1.53-3.12)], heart failure [OR 3.34, IC 95% (1.72-6.48)] and invasive ventilation support requirement [OR: 2.38, IC 95% (1.63-3.50)]. To conclude, HYPO-FU was frequent in the first year after COVID-19 infection, and the risk was higher in older men with comorbidities, increasing rehospitalisation. Further studies aimed at evaluating the beneficial effects of correcting hyponatremia in these patients are warranted.
Subject(s)
Body Fluids , COVID-19 , Heart Failure , Hyponatremia , Aged , Humans , Male , COVID-19/complications , COVID-19/epidemiology , Follow-Up Studies , Hyponatremia/epidemiology , Hyponatremia/etiologyABSTRACT
BACKGROUND: Therapeutic drug monitoring (TDM) of infliximab has been shown to be a effective strategy for inflammatory bowel disease (IBD). Population pharmacokinetic (PopPK) modeling can predict trough concentrations for individualized dosing. OBJECTIVE: The aim of this study was to develop a PopPK model of infliximab in a paediatric population with IBD, assessing the effect of single nucleotide polymorphisms (SNPs) and other biomarkers on infliximab clearance. METHODS: This observational and ambispective single-centre study was conducted in paediatric patients with IBD treated with infliximab between July 2016 and July 2022 in the Paediatric Gastroenterology Service of the Hospital Universitari Vall d'Hebron (HUVH) (Spain). Demographic, clinical, and analytical variables were collected. Twenty SNPs potentially associated with variations in the response to infliximab plasma concentrations were analysed. infliximab serum concentrations and antibodies to infliximab (ATI) were determined by ELISA. PopPK modelling was performed using nonlinear mixed-effects analysis (NONMEM). RESULTS: Thirty patients (21 males) were included. The median age (range) at the start of infliximab treatment was 13 years (16 months to 16 years). A total of 190 samples were obtained for model development (49 [25.8%] during the induction phase). The pharmacokinetics (PK) of infliximab were described using a two-compartment model. Weight, erythrocyte sedimentation rate (ESR), faecal calprotectin (FC), and the SNP rs1048610 (ADAM17) showed statistical significance for clearance (CL), and albumin for inter-compartmental clearance (Q). Estimates of CL1 (genotype 1-AA), CL2 (genotype 2-AG), CL3 (genotype 3-GG), Q, Vc, and Vp (central and peripheral distribution volumes) were 0.0066 L/h/46.4 kg, 0.0055 L/h/46.4 kg, 0.0081 L/h/46.4 kg, 0.0029 L/h/46.4 kg, 0.6750 L/46.4 kg, and 1.19 L/46.4 kg, respectively. The interindividual variability (IIV) estimates for clearance, Vc, and Vp were 19.33, 16.42, and 36.02%, respectively. CONCLUSIONS: A popPK model utilising weight, albumin, FC, ESR, and the SNP rs1048610 accurately predicted infliximab trough concentrations in children with IBD.
Subject(s)
Biomarkers , Drug Monitoring , Inflammatory Bowel Diseases , Infliximab , Polymorphism, Single Nucleotide , Humans , Infliximab/pharmacokinetics , Infliximab/therapeutic use , Child , Male , Adolescent , Female , Child, Preschool , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/genetics , Biomarkers/blood , Drug Monitoring/methods , Infant , Gastrointestinal Agents/pharmacokinetics , Gastrointestinal Agents/therapeutic use , Models, Biological , SpainABSTRACT
BACKGROUND AND OBJECTIVE: The gold standard treatment of established cytomegalovirus infection or prevention in solid organ transplantation is the intravenous administration of ganciclovir (GCV) or oral administration of valganciclovir (VGCV), both adjusted to the renal function. In both instances, there is a high interindividual pharmacokinetic variability, mainly owing to the wide range of variation of both the renal function and body weight. Therefore, accurate estimation of the renal function is crucial for GCV/VGCV dose optimization. This study aimed to compare three different formulas for estimating the renal function in solid organ transplantation patients with cytomegalovirus infection, for individualizing antiviral therapy with GCV/VGCV, using a population approach. METHODS: A population pharmacokinetic analysis was performed using NONMEM 7.4. A total of 650 plasma concentrations obtained after intravenous GCV and oral VGCV administrations were analyzed, from intensive and sparse sampling designs. Three different population pharmacokinetic models were built with the renal function given by Cockcroft-Gault, Modification of Diet in Renal Disease, or Chronic Kidney Disease EPIdemiology Collaboration (CKD-EPI) formulas. Pharmacokinetic parameters were allometrically scaled to body weight. RESULTS: The CKD-EPI formula was identified as the best predictor of between-patient variability in GCV clearance. Internal and external validation techniques showed that the CKD-EPI model had better stability and performed better compared with the others. CONCLUSIONS: The model based on the more accurate estimation of the renal function with the CKD-EPI formula and body weight as a size metric most used in the clinical practice can refine initial dose recommendations and contribute to GCV and VGCV dose individualization when required in the prevention or treatment of cytomegalovirus infection in solid organ transplantation patients.
Subject(s)
Cytomegalovirus Infections , Organ Transplantation , Renal Insufficiency, Chronic , Humans , Ganciclovir/pharmacokinetics , Ganciclovir/therapeutic use , Valganciclovir , Antiviral Agents/pharmacokinetics , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/prevention & control , Renal Insufficiency, Chronic/drug therapy , Kidney/physiologyABSTRACT
OBJECTIVES: To monitor the early emergence of genetic mutations related to reduced susceptibility to monoclonal anti-body (mAb)-based treatment in immunocompromised patients with long-term viral excretion using whole-genome sequencing at a tertiary university hospital in Barcelona, Spain. METHODS: Serial severe acute respiratory syndrome coronavirus 2-positive samples (mid-December 2021-mid-March 2022) from eight immunosuppressed, fully vaccinated patients (for solid-organ transplantation or haematologic malignancies) with long-term viral excretion despite undergoing mAb therapy (sotrovimab) for coronavirus disease 2019 were selected. Whole-genome sequencing was performed following the ARTIC, version 4.1, protocol on the MiSeq platform. Mutations in the coding sequence of the spike protein with a frequency of ≥5% were studied. RESULTS: A total of 37 samples from the studied cases were analysed. All the cases, except one, were confirmed to have the Omicron variant BA.1; one had Delta (AY.100). Thirty-four different mutations were detected within the receptor-binding domain of the spike protein in 62.5% of patients, eight of which were not lineage related and located in the sotrovimab target epitope (P337L, E340D, E340R, E340K, E340V, E340Q, R346T and K356T). Except for P337L, all changes showed a significant increase in frequency or fixation after the administration of sotrovimab. Some of them have been associated with either reduced susceptibility to mAb therapy, such as those at position 340, or the acquisition of a new glycosylation site (346 and 356 positions). CONCLUSIONS: This study highlights the importance of monitoring for early in vivo selection of mutations associated with reduced susceptibility to mAb therapy, especially in immunocompromised patients receiving anti-viral drugs, whose immune response is not able to control viral replication, resulting in long-term viral shedding, and those receiving selective evolution pressure. Virologic surveillance of genetically resistant viruses to available anti-viral therapies is considered a priority for both patients and the community.
Subject(s)
COVID-19 , Drug Resistance, Viral , Immunocompromised Host , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Virus Shedding , Humans , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/genetics , COVID-19/immunology , Mutation , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Drug Resistance, Viral/genetics , Immunocompromised Host/immunology , Virus Shedding/genetics , Virus Shedding/immunologyABSTRACT
OBJECTIVE: The purpose of this systematic review is to analyze the published data on the efficacy and safety of doses higher than 180 mg/m2 of irinotecan recommended in the drug's summary of product characteristics in metastatic colorectal cancer patients with genotypes UGT1A1*1/*1 or *1/*28 who are treated with the FOLFIRI regimen. METHOD: A systematic review of the literature was carried out in Medline and Embase searching for articles published up to December 2021. The methods used were based on the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The criteria for the inclusion of studies were previously defined based on the two secondary goals addressed in this review: 1) To analyze the magnitude of the differences in clinical responses and 2) To study the magnitude of the differences in adverse effects of irinotecan at high doses, as compared to the doses described in the summary of product characteristics corresponding to the FOLFIRI regimen in patients with metastatic colorectal cancer with genotypes UGT1A1*1/* 1 or *1/*28. RESULTS: The search yielded a total of 985 references, of which 13 were selected for analysis. Seven evaluated both efficacy and safety and six only safety. With regard to the studies that evaluated both efficacy and safety, six out of seven (85.7%) were in favor of increasing irinotecan dose according to the objective response rate and progression-free survival. Two of them even recommended dose increases based on overall survival. Irinotecan safety studies suggest that doses higher than 180 mg/m2 are tolerated by most UGT1A1*1/*1 and *1/*28 patients. CONCLUSIONS: The present systematic review shows the advisability of considering adjusting the dose of irinotecan when used as part of the FOLFIRI regimen based on the polymorphisms of the UGT1A1 gene as this may increase the likelihood of an adequate clinical response.
OBJETIVO: El objetivo de la presente revisión sistemática es analizar los datos publicados sobre la eficacia y seguridad de las dosis superiores a los 180 mg/m2 de irinotecán recomendadas en la ficha técnica en pacientes con cáncer colorrectal metastásico tratados con el esquema FOLFIRI y con genotipo UGT1A1*1/*1 y *1/*28.Método: Se realizó una revisión sistemática mediante una búsqueda bibliográfica en Medline y Embase de los artículos publicados hasta diciembre de 2021. Los métodos utilizados se basaron en los recomendados según Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Los criterios para la inclusión de los estudios se definieron previamente en base a los dos objetivos secundarios que aborda esta revisión: 1) Analizar la magnitud de la diferencia de la respuesta clínica y 2) estudiar la magnitud de la diferencia de los efectos dversos a irinotecán a dosis altas, en comparación con las dosis descritas en la ficha técnica para el esquema FOLFIRI en pacientes con cáncer colorrectal metastásico con el genotipo UGT1A1*1/*1 o *1/*28. RESULTADOS: La estrategia de búsqueda reportó un total de 98 referencias, de las que 13 fueron seleccionadas para el análisis, 7 (53,8%) evaluando tanto eficacia como seguridad y 6 (46,2%) únicamente seguridad. En relación con los estudios que evaluaron eficacia y seguridad, 6 (85,7%) se mostraron favorables al aumento de dosis en términos de tasa de respuesta objetiva y supervivencia libre de progresión e, incluso, en 2 de ellos en supervivencia global. Los estudios que evaluaron seguridad apuntan a que dosis de irinotecán superiores a 180 mg/m2 son toleradas por la mayor parte de los pacientes UGT1A1*1/*1 y *1/*28. CONCLUSIONES: La presente revisión sistemática muestra la conveniencia de valorar el ajuste de dosis de irinotecán dentro del esquema FOLFIRI en función de los polimorfismos del gen UGT1A1, con un potencial aumento de las probabilidades de una adecuada respuesta clínica.
Subject(s)
Camptothecin , Colorectal Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/adverse effects , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Fluorouracil/adverse effects , Genotype , Glucuronosyltransferase/genetics , Glucuronosyltransferase/therapeutic use , Humans , Irinotecan/adverse effects , Leucovorin/adverse effectsABSTRACT
Objectives: Administration of busulfan is extending rapidly as a part of a conditioning regimen in patients undergoing hematopoietic stem cell transplantation (HSCT). Monitoring blood plasma levels of busulfan is recommended for identifying the optimal dose in patients and for minimizing toxicity. The aim of this research was to validate a simple, rapid, and cost-effective analytical tool for measuring busulfan in human plasma that would be suitable for routine clinical use. This novel tool was based on liquid chromatography coupled to mass spectrometry. Methods: Human plasma samples were prepared using a one-step protein precipitation protocol. These samples were then resolved by isocratic elution in a C18 column. The mobile phase consisted 2 mM ammonium acetate and 0.1% formic acid dissolved in a 30:70 ratio of methanol/water. Busulfan-d8 was used as the internal standard. Results: The run time was optimized at 1.6 min. Standard curves were linear from 0.03 to 5 mg/L. The coefficient of variation (%CV) was less than 8%. The accuracy of this method had an acceptable bias that fell within 85-115% range. No interference between busulfan and the interfering compound hemoglobin, lipemia, or bilirubin not even at the highest concentrations of compound was tested. Neither carryover nor matrix effects were observed using this method. The area under the plasma drug concentration-time curves obtained for 15 pediatric patients who received busulfan therapy prior to HSCT were analyzed and correlated properly with the administered doses. Conclusions: This method was successfully validated and was found to be robust enough for therapeutic drug monitoring in a clinical setting.
ABSTRACT
OBJECTIVES: To evaluate the potential association between chronic exposure to medication and death related to COVID-19. METHODS: This is a retrospective cross-sectional study that included all patients hospitalised due to COVID-19 from 11 March to 4 June 2020 in our centre. Chronic patient medication was classified by the Anatomical Therapeutic Chemical (ATC) classification; demographic and clinical data were analysed. Multivariate logistic regression models were used to estimate the adjusted odds ratios (aOR) of death for each drug exposure; each aOR represents an independent model adjusted by clinical factors related to COVID-19 mortality. RESULTS: The study included 978 patients with a mean (SD) age of 64.5 (17.7) years who were predominantly male (531, 54.3%). Of all 978 patients, 182 (18.61%) died during the follow-up of the study. The most common Charlson Comorbidity Index (CCI) was 0, 4.2% were smokers, 16.7% were obese, 47.4% had hypertension, and 19.4% were diabetic. Most patients (70.8%) were prescribed at least one treatment, 32.5% used >5 treatments, and 8.6% >10. Our data suggest that COVID-19 hospitalised patients taking trimethoprim and analogues, leukotriene receptor antagonists, calcineurin inhibitors, aldosterone antagonists, selective immunosuppressants, propulsives, insulins and analogues, and benzodiazepine derivatives have a higher risk of death. CONCLUSIONS: This study investigated the association between chronic exposure to drugs and the risk of death in COVID-19 patients. Our results have shed some light on the impact of chronic drug exposure on the risk of severe COVID-19; however, further research is needed to increase the understanding about its relevance.
ABSTRACT
The emergency of the coronavirus disease 2019 (COVID-19) pandemic led to the off-label use of drugs without data on their toxicity profiles in patients with COVID-19, or on their concomitant use. Patients included in the COVID-19 Patient Registry of a tertiary hospital during the first wave were analyzed to evaluate the adverse drug reactions (ADRs) with the selected treatments. Twenty-one percent of patients (197 out of 933) had at least one ADR, with a total of 240 ADRs. Patients with ADRs were more commonly treated with multiple drugs for COVID-19 infection than patients without ADRs (p < 0.001). They were younger (median 62 years vs. 70.1 years; p < 0.001) and took less medication regularly (69.5% vs. 75.7%; p = 0.031). The most frequent ADRs were gastrointestinal (67.1%), hepatobiliary (10.8%), and cardiac disorders (3.3%). Drugs more frequently involved included lopinavir/ritonavir (82.2%), hydroxychloroquine (72.1%), and azithromycin (66.5%). Although most ADRs recovered without sequelae, fatal cases were described, even though the role of the disease could not be completely ruled out. In similar situations, efforts should be made to use the drugs in the context of clinical trials, and to limit off-label use to those drugs with a better benefit/risk profile in specific situations and for patients at high risk of poor disease prognosis.
ABSTRACT
BACKGROUND: Modulation of the immune system to prevent lung injury is being widely used against the new coronavirus disease (COVID-19). The primary endpoint was mortality at 7 days after tocilizumab administration. Secondary endpoints were admission to the intensive care unit, development of ARDS and respiratory insufficiency among others. METHODS: We report the preliminary results from the Vall d'Hebron cohort study at Vall d'Hebron University Hospital, in Barcelona (Spain), including all consecutive patients who had a confirmed SARS-CoV-2 infection and who were treated with tocilizumab until March 25th. RESULTS: 82 patients with COVID-19 received at least one dose of tocilizumab. The mean (± SD) age was 59.1 (19.8) years, 63% were male, 22% were of non-Spanish ancestry, and the median (IQR) age-adjusted Charlson index at baseline was 3 (1-4) points. Respiratory failure and ARDS developed in 62 (75.6%) and 45 (54.9%) patients, respectively. Median time from symptom onset to ARDS development was 8 (5-11) days. Mortality at 7 days was 26.8%. Hazard ratio for mortality was 3.3; 95% CI, 1.3-8.5 (age-adjusted hazard ratio for mortality 2.1; 95% CI, 0.8-5.8) if tocilizumab was administered after the onset of ARDS. CONCLUSION: Early administration of tocilizumab in patients needing oxygen supplementation may be critical to patient recovery. Our preliminary data could inform bedside decisions until more data regarding the precise timing in of initiation of the treatment with tocilizumab.
Subject(s)
COVID-19 Drug Treatment , Respiratory Distress Syndrome , Respiratory Insufficiency , Adult , Antibodies, Monoclonal, Humanized , Cohort Studies , Female , Humans , Male , Middle Aged , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Respiratory Insufficiency/etiology , Respiratory Insufficiency/therapy , SARS-CoV-2 , Treatment OutcomeABSTRACT
Background: Modulation of the immune system to prevent lung injury is being widely used against the new coronavirus disease (COVID-19). The primary endpoint was mortality at 7 days after tocilizumab administration. Secondary endpoints were admission to the intensive care unit, development of ARDS and respiratory insufficiency among others. Methods: We report the preliminary results from the Vall d'Hebron cohort study at Vall d'Hebron University Hospital, in Barcelona (Spain), including all consecutive patients who had a confirmed SARS-CoV-2 infection and who were treated with tocilizumab until March 25th. Results: 82 patients with COVID-19 received at least one dose of tocilizumab. The mean (± SD) age was 59.1 (19.8) years, 63% were male, 22% were of non-Spanish ancestry, and the median (IQR) age-adjusted Charlson index at baseline was 3 (1-4) points. Respiratory failure and ARDS developed in 62 (75.6%) and 45 (54.9%) patients, respectively. Median time from symptom onset to ARDS development was 8 (5-11) days. Mortality at 7 days was 26.8%. Hazard ratio for mortality was 3.3; 95% CI, 1.3-8.5 (age-adjusted hazard ratio for mortality 2.1; 95% CI, 0.8-5.8) if tocilizumab was administered after the onset of ARDS. Conclusion: Early administration of tocilizumab in patients needing oxygen supplementation may be critical to patient recovery. Our preliminary data could inform bedside decisions until more data regarding the precise timing in of initiation of the treatment with tocilizumab.
Antecedentes: Los tratamientos inmunomoduladores para la prevención del daño pulmonar están siendo ampliamente estudiados contra la COVID-19. El objetivo primario es evaluar la mortalidad a los 7 días después de la administración de tocilizumab. El objetivo secundario es el ingreso en UCI, el desarrollo de distrés respiratorio agudo e insuficiencia respiratoria aguda entre otros. Métodos: Informamos sobre los resultados preliminares de la cohorte del Hospital Universitario Vall d'Hebron en Barcelona (España), que incluye todos los pacientes consecutivos con infección confirmada por SARS-CoV-2 y que recibieron tratamiento con tocilizumab hasta el 25 de marzo 2020. Resultados: Ochenta y dos pacientes con COVID-19 recibieron al menos una dosis de tocilizumab. La edad media (±DE) fue de 59,1 (±19,8) años, el 63% eran hombres, 22% correspondía a paciente nacidos fuera de España, y la mediana (RIC) del índice de Charlson ajustado por edad en el momento basal fue de 3 (1-4) puntos. Sesenta y dos pacientes (75,6%) y 45 pacientes (54,9%) desarrollaron insuficiencia respiratoria y distrés respiratorio agudo respectivamente. La mediana de tiempo desde el inicio de los síntomas hasta el desarrollo de ditrés fue de 8 días (5-11). La mortalidad a los 7 días fue del 26,8% La hazard ratio de mortalidad fue del 3,3; IC 95% 1,3-8,5 (la hazard ratio de mortalidad ajustada por edad fue de 2,1; IC 95% 0,8-5,8) si el tocilizumab se administraba después del inicio del distrés respiratorio. Conclusión: La administración precoz de tocilizumab en pacientes con suplementos de oxígeno podría ser crítica para la recuperación de los pacientes. Nuestros datos podrían ayudar a tomar decisiones clínicas hasta que se disponga de más información sobre el momento adecuado para iniciar el tratamiento con tocilizumab.